Evaluation of chemotherapy of cancer patients has identified that drugs in certain combinations have been more effective than single agents. It is necessary to employ drugs by a carefully elaborated regimen to provide optimal chemotherapy with the minimal damage to the patient's normal tissues. When more than one drug is used, the parameters delineating effectiveness become increasingly complicated. Such parameters must be understood if we wish to rationally improve those drug combinations. There is a very limited basic information available on the pharmacodynamics of drug combinations, particularly on drug combination for solid tumors. We have chosen to study six drugs, adriamycin, cyclophosphamide, methotrexate, 5-fluorouracil, L-phenylalanine mustard, and methyl-CCNU, each of which alone or in combination has destroyed activity against human solid tumors. Using tumor-bearing mice, we plan to determine the relationship between dosage scheduling during combination chemotherapy and the concentrations of active drug in plasma, tumor, and sensitive tissues. We will also examine the effects of these drugs on macromolecular synthesis in tumors and sensitive tissues during combination chemotherapy. This will serve to provide us information with respect to the physiologic disposition of each drug in relation to tumor growth inhibition and organ toxicity. Simultaneously, in tumor cell culture studies we plan to examine the biochemical effects of these drugs, alone and in combination at the cellular level. With the knowledge obtained from in vivo and in vitro studies we may be able to better understand the enhanced effect obtained during combination cancer chemotherapy. Hopefully, this will lead to rational suggestions for the better use of combinations of anticancer drugs against human solid tumors.